- Email: [email protected]
Intravenous use of enoximone
Intravenous Use of Enoximone MICHAEL
H. CRAWFORD,
MD
significant (p
To assess the efficacy and safety of acute therapy with intravenous enoximone in patjents with severe congestive heart failure, 118 patients from 5 centers were treated with incremental doses following 2 schedules: to a maximum cumulative dose of 3.0 mg/kg (44 patients) and to a maximum cumulative dose of 10.5 mg/kg (74 patients). Both schedules produced significant increases in cardiac index (55% and 68%) p
P
atients with congestive heart failure (CHF) often enter a vicious cycle associated with progressive decompensation that results in hospitalization for severe right- and left-sided heart failure. This vicious cycle is caused by the adverse effects of various compensatory mechanisms that are called into play when cardiac output decreases. Reduced renal perfusion leads to release of aldosterone, which causes further fluid, salt and water retention, larger ventricular end-diastolic volumes, higher wall stress, higher afterload and, ultimately, reduced left ventricular performance. Also, renal hypoperfusion releases renin, which stimulates the formation of angiotensin II, a potent vasoconstrictor. The resultant arterial vasoconstriction increases biood pressure, myocardial wall tension and afterload, resulting in reduced left ventricular performance. Thus, the very mechanisms that the body enacts to compensate for a reduction in left ventricular performance can further reduce function in patients with severe CHF. Such patients are often refractory to oral medications including high dosage furosemide and vasodilator therapy with agents such as captopril.
In this situation, we have found that 48 hours of intensive intravenous therapy with potent inotropic agents, such as dopamine, will break the vicious cycle, initiate a diuresis and, ultimately, shorten the patient’s hospital stay.l After this treatment, patients respond more readily to oral medication and often remain out of hospital for longer periods of time than before. The major drawback to this form of therapy is that dopamine and other synthetic catecholamines must be used in very low dosages to avoid further vasoconstrictor effects. Therefore, there is considerable interest in using the nonglycosidic, noncatecholamine agent enoximone, which possesses both positive inotropic and vasodilator effects, for this purpose.z-9 In this article, the results of a multicenter trial of short-term intravenous enoximone are presented. Five centers were part of this study group (see Appendix). The combined data for this report were providedb by Merrell Dow Laboratories.
Methods and Patients From 5 centers in the U.S., 119 patients in New York Heart Association class III to IV CHF were entered into a study of the acute hemodynamic effects of incremental doses of enoximone. The principal admission criteria were a cardiac index of <2.5 liters/min/ m2 and a pulmonary capillary wedge pressure of >15 mm Hg on right-sided heart catheterization. Exclusion criteria included shock [systolic blood pressure <90 mm Hg), uncontrolled ventricular tachyarrhythmias, restrictive cardiomyopathy or valvular disease, multi-
From the University of Texas Health Science Center and Veterans Administration Hospital, San Antonio, Texas. This study was supported in part by Merrell Dow Laboratories, Cincinnatti, Ohio, and the Veterans Administration, Washington, D.C. Address for reprints: Michael H. Crawford, MD, Department of Medicine, Division of Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7872. 42C
August
14, 1987
system disease and vasodilator or P-blocker therapy. All patients entered in the study had a history of chronic CHF and were believed to be candidates for more aggressive therapy because of inadequate response to their current medications. Two patients had had an acute myocardial infarction (class II or III] recently. In 1 patient, there was malfunction of the hemodynamic catheter such that hemodynamic data were not available. Data from this patient were included in the safety part of the study only. The 118 patients with hemodynamic data had an average control cardiac index of 1.9 f 0.4 (standard error] liters/min/m2 and pulmonary capillary wedge pressure of 27 f 7 mm Hg. The average duration of heart failure was 3.7 f 4.2 years (range 0.04 to 19). There were 97 men and 21 women ranging in age from 15 to 84 years (mean 59 f 12) Hemodynamic measurements were made using thermodilution Swan Ganz catheters. Baseline measurements were taken 15 minutes apart until a steady state was observed, then drug administration was started in incremental doses every 30 minutes following 2 schedules. The first was to a maximum cumulative dose of 3.0 mg/kg (44 patients); the second to a maximum cumulative dose of 10.5 mg/kg (74 patients]. Enoximone administration was discontinued in both schedules if any of the following predetermined hemodynamic criteria were observed: cardiac output failed to increase by >lO% compared with the previous value; heart rate increased to >l20 beats/min or by a >l5% increase compared with baseline; systolic blood pressure decreased by >20% compared with baseline; pulmonary capillary wedge pressure decreased to
Hemodynamic effects of maximum cumulative dose (Table I): The mean cumulative dose in dosing schedule 1 was 2.2 mg/kg and in schedule 2 it was 4.3 I
Effect
of Enoximone
on Hemodynamic
AMERICAN
JOURNAL
OF CARDIOLOGY
Variables Pts.
Variable
Schedule
Cl (liters/min/m2) PCWP
(mm Hg)
SVR (dynes
s crnm5)
RAP (mm Hg) HR (beats/min) MBP (mm Hg)
1 2 1 2 1 2 1 2 1 2 1 2
Cl = cardiac index: HR = heart rate; MBP = mean RAP = right atrial pressure; SVR = systemic vascular Data are mean f standard error.
Volume
60
43c
mg/kg. The corresponding maximal hemodynamic responses were surprisingly similar despite this more than 2-fold difference in dosing. Cardiac index increased by 55% with schedule 1 and by 68% with schedule 2. Pulmonary capillary wedge pressure decreased by 29% and 4270, respectively, and right atria1 pressure by 30% and 4670. Schedule 1 decreased systemic vascular resistance by 33% and schedule 2 reduced it by 45%. All these changes were statistically significant (p3 mg/kg would rarely be needed to affect a clinical response in patients with severe CHF. Also, changes in heart rate >15% would be more common with cumulative doses >l.5 mg/kg and decreases in mean blood pressure >lO% would be more likely with cumulative doses >3.0 mg/kg. The duration of action of enoximone was evaluated whenever possible after the last dose. The hemodynamic effects were noted to decrease gradually and were still evident for the 6 hour observation period in some patients. The time to peak response could not be estimated, but most patients had effective hemody namic responses within 10 to 30 minutes of the first or second dose of enoximone. Adverse effects (Table III): A total of 24 of the 119 patients who received enoximone (2070) experienced 38 incidents of adverse effects. The relation of these observed adverse effects to the study drugs is difficult to determine because this was an open study without a placebo control and the patients were seriously ill.
Results
TABLE
THE
(n)
Pretreatment
39 72 35 65 43 73 44 73 43 74 44 74
1.84 f .ll 1.98 f .07 27 + 2 26 dz 1 1,885 f 125 1,563 f 92 12 f 2 14f 1 90 f 5 a4 * 2 a7 f 3 60 f 2
blood pressure: resistance.
PCWP
= pulmonary
Posttreatment 2.85 f .I5 3.32 f. .12 19 5 3 15h 1 1,272 f 100 867 f 46 7fl 7fl 95 f 5 95 4z 2 a3 f 4 69 f 2 capillary
wedge
pressure;
44c
A SYMPOSIUM:
TABLE
II
Mean
lHt
VI- tNOXlMONE
ust
Percentage
of Change
IN HEART
in Hemodynamic
FAILURE
Variables
for the First Three
Schedule Cumulative Dose
0.5 1.0 1.5
PCWP (n = 28)
(n 2’33)
WwW
20.6 41.9 51.0
f f f
3.1% 5.4% 5.6%
-11.5 -19.6 -26.2
f 3.5% f 3.8% f 4.2%
SW (n = 37)
f 5.7% f 4.9% f 5.0% Schedule
(n = 49) 0.5 1.5 3.0
31.6 56.4 76.0
Abbreviations
as in Table
f 2.9% f 3.7% f 5.3%
(n = 43) -9.0 -21.9 -28.2
f 3.0% f 3.7% f 3.8%
-10.2 -23.8 -29.2
f f f
1 and 2
f 2.5% f 2.6% f 2.5%
HR (n = 36) 2.8 f 4.9 f 5.3 f
1.0% 1.2% 1.4%
MBP (n = 37) 2.4 f -1.6 f -3.8 f
1.2% 1.5% 1.7%
2
(n = 49) -25.7 -39.0 -43.3
of Schedule
1
RAP (n = 36) -18.3 -36.1 -41.1
Doses
(n = 50)
2.9% 2.7% 4.4%
-15.9 -32.3 -41.3
f 2.1% f 1.5% f 2.1%
(n = 51) 11.9 f 3.4% 15.8 f 3.9% 18.4 f 3.7%
(n = 51) 1.0 f 3.4% -5.2 f 2.9% -10.3 f 2.7%
I.
Also, there was no apparent relation between cumulative dose and any adverse effect. Therefore, the data are combined for the 2 dosing schedules. Cardiovascular side effects were most common (10%). Of note, 4 patients experienced ventricular tachycardia (3.4%) and 3 patients experienced hypotension (2.5%). Central nervous system side effects were the next most frequent (6.7%), followed by gastrointestinal upset (5.0%). Safety laboratory tests: Thirty-three patients (28%) showed a >5% decrease in hemoglobin (>2 g%) and hematocrit (>5%) that were considered to be clinically notable. Whether these changes were related to drug administration, phlebotomy or catheterization procedures was not clear. Eighty-five patients had pre- and posttreatment platelet count tests performed and in 7 of these patients a platelet count below lOO,OOO/pl was noted posttreatment. In 2 patients, the platelet count was below this value before enoximone infusion. The remaining 5 all occurred in patients treated with dosage schedule 2 and were not associated with petechia, purpura or any gross bleeding complications. It should also be noted that 5 patients with low pretreatment values had marked increases in their platelet counts after enoximone administration; therefore, no overall effect on platelet counts was noted. In 62 patients, pre- and posttreatment serum glutamic oxaloacetic transaminase values were availabie and 5 patients showed increases after enoximone administration. One of these patients had a marked elevation before the study. The relation of these findings to drug administration is difficult to determine.
Discussion These studies indicate that intravenous enoximone produces a marked improvement in the hemodynamits of patients with severe CHF with a low incidence of adverse effects. If maximum cumulative loading doses are 13.0 mg/kg, little change in heart rate and blood pressure is observed, despite marked changes in cardiac output and filling pressures. Experiments with animal preparations have suggested that enoximone has both vasodilator and posi-
TABLE Ill Incidence of Adverse Administration (n = 119) Adverse Effect Cardiovascular ventricular tachycardia other arrhythmias hypotension Central nervous system insomnia memory decreased somnolence agitation and anxiety headache Gastrointestinal nausea and vomiting abdominal pain diarrhea Other oliguria urinary retention muscle pain hyperuricemia
Experiences
During
Enoximone
No. of Patients (%) 12 (10.1) 4(3.4) 5(4.2) 3 (2.5) 8 (6.7) 3 (2.5) 2 (1.7) 2 (1.7) 2 (1.7) 1 (0.8) 6 (5.0) 4 (3.4) 1 (0.8) 1 (0.8) 5 (4.2) 1 (0.8) 1 (0.8) 2 (1.7) 1 (0.8)
tive inotropic effects. l”,ll Also, our previous experience with the acute administration of enoximone to patients in the cardiac catheterization laboratory supported the latter effect becuase the first derivative of left ventricular systolic pressure increased significantl~.~ In addition, studies by Amin et a17sghave shown that enoximone and dobutamine produce similar increases in cardiac output and stroke volume but enoximone reduces pulmonary artery and wedge pressures more; enoximone and nitroprusside both decrease pulmonary wedge pressure and systemic venous return equally, but enoximone increases cardiac output more. Therefore, the available data suggest that enoximone does have both positive inotropic and vasodilator properties. The mechanism of action of enoximone at the cellular level may be related to its ability to inhibit phosphodiesterase, which would cause an increase in intracellular cyclic adenosine monophosphate levels.12 There are several new agents with this basic mechanism of action under investigation for the treatment of
August
heart failure. The best known is amrinone, which is now available as a parenteral medication. This agent causes similar hemodynamic effects as enoximone.13 Both drugs can be administered orally, but the oral use of amrinone resulted in significant thrombocytopenia and was withdrawn from further clinical use.14 Enoximone produced no definite adverse hematologic effects in our acute study. Long-term investigations with oral enoximone are in progress. Arrhythmias, nausea and vomiting and insomnia were the most common adverse effects noted in our study. The only serious side effects were ventricular tachycardia (3.4%) and hypotension [2.5%). These were patients, however, with severe CHF who were receiving many other medications. Thus, a direct cause and effect relation cannot be proven and there was no comparison group in this open-label study. Only 1 previously reported experience with intravenous enoximone has shown an increase in ventricular premature beats in 1 of the 8 patients studied.15 This patient also had increased premature beats during a dobutamine infusion. Thus, the increased inotropic effects of enoximone might be expected to increase ventricular arrhythmias in certain susceptible patients. The hemodynamic effects of enoximone decreased gradually after cessation of therapy and had waned sufficiently by 4 hours to consider restarting therapy in most patients. This short biologic half-life suggests that a constant intravenous infusion may be the best way to administer enoximone and recent experience from our laboratory supports this concept.@ Thus, enoximone has considerable promise as a short-term intravenous drug for breaking the vicious cycle of refractory CHF and may be an effective long-term oral agent for preventing decompensation in patients with cardiac failure. Acknowledgment: I appreciate the help of Dr. T. Bekele and his staff at Merrell Dow Laboratories for preparing the multicenter data.
References 1. White, DH, Crawford MH, O’Rourke RA. Beneficial effects of prolonged low dose dopamine in hospitalized patients with severe refractory heart failure. CJin Cardiol 1979;2:1%-159. 2. Uretsky BF, Generalovich T, Reddy PS, Spangenberg RB, Folansbee WP. The acute hemodynamic effects of a new agent, MDL 17,043 in the treatment of congestive heart failure. Circulation 1983;67:823-828. 3. Crawford MH, Richards KL, Sodums M, Kennedy GT. Positive inotropic and vasodilator effects of MDL 17,043 in patients with reduced left ventricu-
14, 1967
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
60
45c
Jar performance. Am T CardioJ 1984;53:1051-1060. 4. Kereiakes D, Chattejee K, Parmley WW, Atherton B, Curran D, Kereiakes A, Spangenberg R. Intravenous and oral MDL 17,043 [a new inotrope-vasodifator agent] in congestive heart failure: hemodynamic and clinical evaluation in 38 patients. /ACC 1984;4:884-889. 5. Amin DK, Shah PK, Hulse S, Shellock FG, Swan HJC. Myocardial metabolic and hemodynamic effects of intravenous MDL 17,043, a new cardiotonic drug, in patients with chronic severe heart failure. Am Heart \1984;108:12851292. 6. Kereiakes DJ, Viquerat C, Lanzer P, Bohrinick EH, Spangenberg R, Buckingham M, Parmley WW, Chattejee K. Mechanisms in improved left ventricular function following intravenous MDL 17,043 in patients with severe chronic heart failure. Am Heart / 1984;108:1278-1284. 7. Amin DK, Shah PK, Shellock FG, Hulse S, Brandon G, Spangenberg R, Swan HJC. Comparative hemodynamic effects of intravenous dobutamine and MDL 17,043, a new cardioactive drug, in severe congestive heart failure. Am Heart [ 1985;109:91-98. 8. Viquerat CE, Kereiakes D, Morris DL, Daly PA, Wexman M, Frank P, Parmley WW, Chattejee K. Alterations in left ventricular function, coronary hemodynamics and myocardiai catecholamine balance with MDL 17,043, a new inotropic vasodilator agent, in patients with severe heart failure. /ACC l985;5:326-332. 9. Amin DK, Shah PK, Hulse S, Shellock F. Comparative acute hemodynamic effects of intravenous sodium nitroprusside and MDL 17,043, a new inotropic drug with vasodilator effects in refractory congestive heart failure. Am Heart J 1985;109:1006-1012. 10. Dage RC, Roebel LE, Hsieh CP, Weiner DL, Woodward JK. CardiovascuJar properties of a new cardiotonic agent: MDL 17,043. T Cardiovasc Pharmacof 1982;4:500-508. 11. Raebel LE, Dage RC, Cheng HC, Woodward JK. Characterization of the cardiovascular activities of a new cardiotonic agent: MDL 17,043. J Cardiovast Phormacol 1982;4:721-729. 12. Kariya T, Willie LJ, Dage RC. Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043: possible involvement of cyclic AMP phosphodiesterase inhibition. [ Cardiovasc Pharmacol 1982:4:509-514. 13. Benotti IR. Grossman W. Braunwald E. Davolos D, Alousi AA. Hemodynamic assessment of amrinone: a new inotropic agent. N EngJ [ Med 1978:2.99:1373-13777. 14. Ansell J, Tiarks C, McCue J, Parrilla N, Benotti JR. Amrinone-induced thrombocytopenia. Arch Intern Med 1984;144:949-952. 15. Likoff MJ. Ulrich S, Hakki A, Iskandrian AB. Comparison of acute hemodynamic response to dobutamine and intravenous MDL 17,043 (enoximone) in severe congestive heart failure secondary to ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Am r CardioJ 1986;57:1328-1334. 16. Ferry DR, Kennedy GT, O’Rourke RA, Crawford MH. Hemodynamic effects of prolonged intravenous therapy with enoximone in patients with severe congestive heart failure. 1 Cardiovasc Pharmacol, in press. APPENDIX Study
Principal
investigators
and Centers
K. Chatterjee, MD University of California at San Francisco, San Francisco, J. N. Cohn, MD University of Minnesota, Minneapolis, Minnesota M. H. Crawford, MD University of Texas Health Science Center, San Antonio, B. Uretsky, MD University of Pittsburgh, Pittsburgh, Pennsylvania K. T. Weber, MD University of Chicago, Chicago, Illinois
in the Multicenter
California
Texas
H. CRAWFORD,
MD
significant (p
To assess the efficacy and safety of acute therapy with intravenous enoximone in patjents with severe congestive heart failure, 118 patients from 5 centers were treated with incremental doses following 2 schedules: to a maximum cumulative dose of 3.0 mg/kg (44 patients) and to a maximum cumulative dose of 10.5 mg/kg (74 patients). Both schedules produced significant increases in cardiac index (55% and 68%) p
P
atients with congestive heart failure (CHF) often enter a vicious cycle associated with progressive decompensation that results in hospitalization for severe right- and left-sided heart failure. This vicious cycle is caused by the adverse effects of various compensatory mechanisms that are called into play when cardiac output decreases. Reduced renal perfusion leads to release of aldosterone, which causes further fluid, salt and water retention, larger ventricular end-diastolic volumes, higher wall stress, higher afterload and, ultimately, reduced left ventricular performance. Also, renal hypoperfusion releases renin, which stimulates the formation of angiotensin II, a potent vasoconstrictor. The resultant arterial vasoconstriction increases biood pressure, myocardial wall tension and afterload, resulting in reduced left ventricular performance. Thus, the very mechanisms that the body enacts to compensate for a reduction in left ventricular performance can further reduce function in patients with severe CHF. Such patients are often refractory to oral medications including high dosage furosemide and vasodilator therapy with agents such as captopril.
In this situation, we have found that 48 hours of intensive intravenous therapy with potent inotropic agents, such as dopamine, will break the vicious cycle, initiate a diuresis and, ultimately, shorten the patient’s hospital stay.l After this treatment, patients respond more readily to oral medication and often remain out of hospital for longer periods of time than before. The major drawback to this form of therapy is that dopamine and other synthetic catecholamines must be used in very low dosages to avoid further vasoconstrictor effects. Therefore, there is considerable interest in using the nonglycosidic, noncatecholamine agent enoximone, which possesses both positive inotropic and vasodilator effects, for this purpose.z-9 In this article, the results of a multicenter trial of short-term intravenous enoximone are presented. Five centers were part of this study group (see Appendix). The combined data for this report were providedb by Merrell Dow Laboratories.
Methods and Patients From 5 centers in the U.S., 119 patients in New York Heart Association class III to IV CHF were entered into a study of the acute hemodynamic effects of incremental doses of enoximone. The principal admission criteria were a cardiac index of <2.5 liters/min/ m2 and a pulmonary capillary wedge pressure of >15 mm Hg on right-sided heart catheterization. Exclusion criteria included shock [systolic blood pressure <90 mm Hg), uncontrolled ventricular tachyarrhythmias, restrictive cardiomyopathy or valvular disease, multi-
From the University of Texas Health Science Center and Veterans Administration Hospital, San Antonio, Texas. This study was supported in part by Merrell Dow Laboratories, Cincinnatti, Ohio, and the Veterans Administration, Washington, D.C. Address for reprints: Michael H. Crawford, MD, Department of Medicine, Division of Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7872. 42C
August
14, 1987
system disease and vasodilator or P-blocker therapy. All patients entered in the study had a history of chronic CHF and were believed to be candidates for more aggressive therapy because of inadequate response to their current medications. Two patients had had an acute myocardial infarction (class II or III] recently. In 1 patient, there was malfunction of the hemodynamic catheter such that hemodynamic data were not available. Data from this patient were included in the safety part of the study only. The 118 patients with hemodynamic data had an average control cardiac index of 1.9 f 0.4 (standard error] liters/min/m2 and pulmonary capillary wedge pressure of 27 f 7 mm Hg. The average duration of heart failure was 3.7 f 4.2 years (range 0.04 to 19). There were 97 men and 21 women ranging in age from 15 to 84 years (mean 59 f 12) Hemodynamic measurements were made using thermodilution Swan Ganz catheters. Baseline measurements were taken 15 minutes apart until a steady state was observed, then drug administration was started in incremental doses every 30 minutes following 2 schedules. The first was to a maximum cumulative dose of 3.0 mg/kg (44 patients); the second to a maximum cumulative dose of 10.5 mg/kg (74 patients]. Enoximone administration was discontinued in both schedules if any of the following predetermined hemodynamic criteria were observed: cardiac output failed to increase by >lO% compared with the previous value; heart rate increased to >l20 beats/min or by a >l5% increase compared with baseline; systolic blood pressure decreased by >20% compared with baseline; pulmonary capillary wedge pressure decreased to
Hemodynamic effects of maximum cumulative dose (Table I): The mean cumulative dose in dosing schedule 1 was 2.2 mg/kg and in schedule 2 it was 4.3 I
Effect
of Enoximone
on Hemodynamic
AMERICAN
JOURNAL
OF CARDIOLOGY
Variables Pts.
Variable
Schedule
Cl (liters/min/m2) PCWP
(mm Hg)
SVR (dynes
s crnm5)
RAP (mm Hg) HR (beats/min) MBP (mm Hg)
1 2 1 2 1 2 1 2 1 2 1 2
Cl = cardiac index: HR = heart rate; MBP = mean RAP = right atrial pressure; SVR = systemic vascular Data are mean f standard error.
Volume
60
43c
mg/kg. The corresponding maximal hemodynamic responses were surprisingly similar despite this more than 2-fold difference in dosing. Cardiac index increased by 55% with schedule 1 and by 68% with schedule 2. Pulmonary capillary wedge pressure decreased by 29% and 4270, respectively, and right atria1 pressure by 30% and 4670. Schedule 1 decreased systemic vascular resistance by 33% and schedule 2 reduced it by 45%. All these changes were statistically significant (p
Results
TABLE
THE
(n)
Pretreatment
39 72 35 65 43 73 44 73 43 74 44 74
1.84 f .ll 1.98 f .07 27 + 2 26 dz 1 1,885 f 125 1,563 f 92 12 f 2 14f 1 90 f 5 a4 * 2 a7 f 3 60 f 2
blood pressure: resistance.
PCWP
= pulmonary
Posttreatment 2.85 f .I5 3.32 f. .12 19 5 3 15h 1 1,272 f 100 867 f 46 7fl 7fl 95 f 5 95 4z 2 a3 f 4 69 f 2 capillary
wedge
pressure;
44c
A SYMPOSIUM:
TABLE
II
Mean
lHt
VI- tNOXlMONE
ust
Percentage
of Change
IN HEART
in Hemodynamic
FAILURE
Variables
for the First Three
Schedule Cumulative Dose
0.5 1.0 1.5
PCWP (n = 28)
(n 2’33)
WwW
20.6 41.9 51.0
f f f
3.1% 5.4% 5.6%
-11.5 -19.6 -26.2
f 3.5% f 3.8% f 4.2%
SW (n = 37)
f 5.7% f 4.9% f 5.0% Schedule
(n = 49) 0.5 1.5 3.0
31.6 56.4 76.0
Abbreviations
as in Table
f 2.9% f 3.7% f 5.3%
(n = 43) -9.0 -21.9 -28.2
f 3.0% f 3.7% f 3.8%
-10.2 -23.8 -29.2
f f f
1 and 2
f 2.5% f 2.6% f 2.5%
HR (n = 36) 2.8 f 4.9 f 5.3 f
1.0% 1.2% 1.4%
MBP (n = 37) 2.4 f -1.6 f -3.8 f
1.2% 1.5% 1.7%
2
(n = 49) -25.7 -39.0 -43.3
of Schedule
1
RAP (n = 36) -18.3 -36.1 -41.1
Doses
(n = 50)
2.9% 2.7% 4.4%
-15.9 -32.3 -41.3
f 2.1% f 1.5% f 2.1%
(n = 51) 11.9 f 3.4% 15.8 f 3.9% 18.4 f 3.7%
(n = 51) 1.0 f 3.4% -5.2 f 2.9% -10.3 f 2.7%
I.
Also, there was no apparent relation between cumulative dose and any adverse effect. Therefore, the data are combined for the 2 dosing schedules. Cardiovascular side effects were most common (10%). Of note, 4 patients experienced ventricular tachycardia (3.4%) and 3 patients experienced hypotension (2.5%). Central nervous system side effects were the next most frequent (6.7%), followed by gastrointestinal upset (5.0%). Safety laboratory tests: Thirty-three patients (28%) showed a >5% decrease in hemoglobin (>2 g%) and hematocrit (>5%) that were considered to be clinically notable. Whether these changes were related to drug administration, phlebotomy or catheterization procedures was not clear. Eighty-five patients had pre- and posttreatment platelet count tests performed and in 7 of these patients a platelet count below lOO,OOO/pl was noted posttreatment. In 2 patients, the platelet count was below this value before enoximone infusion. The remaining 5 all occurred in patients treated with dosage schedule 2 and were not associated with petechia, purpura or any gross bleeding complications. It should also be noted that 5 patients with low pretreatment values had marked increases in their platelet counts after enoximone administration; therefore, no overall effect on platelet counts was noted. In 62 patients, pre- and posttreatment serum glutamic oxaloacetic transaminase values were availabie and 5 patients showed increases after enoximone administration. One of these patients had a marked elevation before the study. The relation of these findings to drug administration is difficult to determine.
Discussion These studies indicate that intravenous enoximone produces a marked improvement in the hemodynamits of patients with severe CHF with a low incidence of adverse effects. If maximum cumulative loading doses are 13.0 mg/kg, little change in heart rate and blood pressure is observed, despite marked changes in cardiac output and filling pressures. Experiments with animal preparations have suggested that enoximone has both vasodilator and posi-
TABLE Ill Incidence of Adverse Administration (n = 119) Adverse Effect Cardiovascular ventricular tachycardia other arrhythmias hypotension Central nervous system insomnia memory decreased somnolence agitation and anxiety headache Gastrointestinal nausea and vomiting abdominal pain diarrhea Other oliguria urinary retention muscle pain hyperuricemia
Experiences
During
Enoximone
No. of Patients (%) 12 (10.1) 4(3.4) 5(4.2) 3 (2.5) 8 (6.7) 3 (2.5) 2 (1.7) 2 (1.7) 2 (1.7) 1 (0.8) 6 (5.0) 4 (3.4) 1 (0.8) 1 (0.8) 5 (4.2) 1 (0.8) 1 (0.8) 2 (1.7) 1 (0.8)
tive inotropic effects. l”,ll Also, our previous experience with the acute administration of enoximone to patients in the cardiac catheterization laboratory supported the latter effect becuase the first derivative of left ventricular systolic pressure increased significantl~.~ In addition, studies by Amin et a17sghave shown that enoximone and dobutamine produce similar increases in cardiac output and stroke volume but enoximone reduces pulmonary artery and wedge pressures more; enoximone and nitroprusside both decrease pulmonary wedge pressure and systemic venous return equally, but enoximone increases cardiac output more. Therefore, the available data suggest that enoximone does have both positive inotropic and vasodilator properties. The mechanism of action of enoximone at the cellular level may be related to its ability to inhibit phosphodiesterase, which would cause an increase in intracellular cyclic adenosine monophosphate levels.12 There are several new agents with this basic mechanism of action under investigation for the treatment of
August
heart failure. The best known is amrinone, which is now available as a parenteral medication. This agent causes similar hemodynamic effects as enoximone.13 Both drugs can be administered orally, but the oral use of amrinone resulted in significant thrombocytopenia and was withdrawn from further clinical use.14 Enoximone produced no definite adverse hematologic effects in our acute study. Long-term investigations with oral enoximone are in progress. Arrhythmias, nausea and vomiting and insomnia were the most common adverse effects noted in our study. The only serious side effects were ventricular tachycardia (3.4%) and hypotension [2.5%). These were patients, however, with severe CHF who were receiving many other medications. Thus, a direct cause and effect relation cannot be proven and there was no comparison group in this open-label study. Only 1 previously reported experience with intravenous enoximone has shown an increase in ventricular premature beats in 1 of the 8 patients studied.15 This patient also had increased premature beats during a dobutamine infusion. Thus, the increased inotropic effects of enoximone might be expected to increase ventricular arrhythmias in certain susceptible patients. The hemodynamic effects of enoximone decreased gradually after cessation of therapy and had waned sufficiently by 4 hours to consider restarting therapy in most patients. This short biologic half-life suggests that a constant intravenous infusion may be the best way to administer enoximone and recent experience from our laboratory supports this concept.@ Thus, enoximone has considerable promise as a short-term intravenous drug for breaking the vicious cycle of refractory CHF and may be an effective long-term oral agent for preventing decompensation in patients with cardiac failure. Acknowledgment: I appreciate the help of Dr. T. Bekele and his staff at Merrell Dow Laboratories for preparing the multicenter data.
References 1. White, DH, Crawford MH, O’Rourke RA. Beneficial effects of prolonged low dose dopamine in hospitalized patients with severe refractory heart failure. CJin Cardiol 1979;2:1%-159. 2. Uretsky BF, Generalovich T, Reddy PS, Spangenberg RB, Folansbee WP. The acute hemodynamic effects of a new agent, MDL 17,043 in the treatment of congestive heart failure. Circulation 1983;67:823-828. 3. Crawford MH, Richards KL, Sodums M, Kennedy GT. Positive inotropic and vasodilator effects of MDL 17,043 in patients with reduced left ventricu-
14, 1967
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
60
45c
Jar performance. Am T CardioJ 1984;53:1051-1060. 4. Kereiakes D, Chattejee K, Parmley WW, Atherton B, Curran D, Kereiakes A, Spangenberg R. Intravenous and oral MDL 17,043 [a new inotrope-vasodifator agent] in congestive heart failure: hemodynamic and clinical evaluation in 38 patients. /ACC 1984;4:884-889. 5. Amin DK, Shah PK, Hulse S, Shellock FG, Swan HJC. Myocardial metabolic and hemodynamic effects of intravenous MDL 17,043, a new cardiotonic drug, in patients with chronic severe heart failure. Am Heart \1984;108:12851292. 6. Kereiakes DJ, Viquerat C, Lanzer P, Bohrinick EH, Spangenberg R, Buckingham M, Parmley WW, Chattejee K. Mechanisms in improved left ventricular function following intravenous MDL 17,043 in patients with severe chronic heart failure. Am Heart / 1984;108:1278-1284. 7. Amin DK, Shah PK, Shellock FG, Hulse S, Brandon G, Spangenberg R, Swan HJC. Comparative hemodynamic effects of intravenous dobutamine and MDL 17,043, a new cardioactive drug, in severe congestive heart failure. Am Heart [ 1985;109:91-98. 8. Viquerat CE, Kereiakes D, Morris DL, Daly PA, Wexman M, Frank P, Parmley WW, Chattejee K. Alterations in left ventricular function, coronary hemodynamics and myocardiai catecholamine balance with MDL 17,043, a new inotropic vasodilator agent, in patients with severe heart failure. /ACC l985;5:326-332. 9. Amin DK, Shah PK, Hulse S, Shellock F. Comparative acute hemodynamic effects of intravenous sodium nitroprusside and MDL 17,043, a new inotropic drug with vasodilator effects in refractory congestive heart failure. Am Heart J 1985;109:1006-1012. 10. Dage RC, Roebel LE, Hsieh CP, Weiner DL, Woodward JK. CardiovascuJar properties of a new cardiotonic agent: MDL 17,043. T Cardiovasc Pharmacof 1982;4:500-508. 11. Raebel LE, Dage RC, Cheng HC, Woodward JK. Characterization of the cardiovascular activities of a new cardiotonic agent: MDL 17,043. J Cardiovast Phormacol 1982;4:721-729. 12. Kariya T, Willie LJ, Dage RC. Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043: possible involvement of cyclic AMP phosphodiesterase inhibition. [ Cardiovasc Pharmacol 1982:4:509-514. 13. Benotti IR. Grossman W. Braunwald E. Davolos D, Alousi AA. Hemodynamic assessment of amrinone: a new inotropic agent. N EngJ [ Med 1978:2.99:1373-13777. 14. Ansell J, Tiarks C, McCue J, Parrilla N, Benotti JR. Amrinone-induced thrombocytopenia. Arch Intern Med 1984;144:949-952. 15. Likoff MJ. Ulrich S, Hakki A, Iskandrian AB. Comparison of acute hemodynamic response to dobutamine and intravenous MDL 17,043 (enoximone) in severe congestive heart failure secondary to ischemic cardiomyopathy or idiopathic dilated cardiomyopathy. Am r CardioJ 1986;57:1328-1334. 16. Ferry DR, Kennedy GT, O’Rourke RA, Crawford MH. Hemodynamic effects of prolonged intravenous therapy with enoximone in patients with severe congestive heart failure. 1 Cardiovasc Pharmacol, in press. APPENDIX Study
Principal
investigators
and Centers
K. Chatterjee, MD University of California at San Francisco, San Francisco, J. N. Cohn, MD University of Minnesota, Minneapolis, Minnesota M. H. Crawford, MD University of Texas Health Science Center, San Antonio, B. Uretsky, MD University of Pittsburgh, Pittsburgh, Pennsylvania K. T. Weber, MD University of Chicago, Chicago, Illinois
in the Multicenter
California
Texas